One of the consequences of the development of improved therapies for the treatment of HIV infection and the acquired immunodeficiency syndrome, and the associated longer survival of infected patients, has been the emergence of diseases such as myocarditis and/or dilated cardiomyopathy (DCM). A number of etiological agents have been proposed to be responsible for the initiation of the pathologic processes leading to the development of myocarditis and DCM in HIV-infected patients. These have included infection of myocytes with HIV or cardiotropic viruses, or cardiotoxicity resulting from drugs commonly used by AIDS patients, such as AZT. Monotherapy with AZT is uncommon today because highly active antiretroviral therapy (HAART) is a formidable clinical combination. However, AZT has been reported to cause a mitochondrial skeletal myopathy, similar to inherited skeletal myopathies, as well as myopathies secondary to inherited cardiomyopathies. Dystrophin was identified as the gene responsible for cardiomyopathy in patients with X-linked cardiomyopathy (XLCM). Dystrophin is thought to provide structural support for the myocyte and cardiomyocyte membrane. Mutations in dystrophin or dystrophin associated protein subcomplexes result in a wide spectrum of skeletal myopathy and/or cardiomyopathy in humans and animal models such as the mouse or hamster. We have recently shown in patients with DCM or ischemic cardiomyopathy that dystrophin remodeling is a useful indicator of left ventricular function. It has been reported that the 2A protease of Coxsackievirus B3, a major etiologic agent of acquired DCM, is capable of cleaving dystrophin, resulting in sarcolemmal disruption in infected mouse hearts. Further, in murine models of DCM defects in the integrity of dystrophin and/or other components of the cytoskeleton may be important in disease pathogenesis in these models. In order to further delineate the role of cytoskeletal disruption in models of acquired DCM we are proposing the following specific aims: Specific Aim 1: Delineation of the events leading to disruption of the cytoskeleton in transgenic mice. Specific Aim 2: Characterization of the cytoskeleton in HAART-treated transgenic mice. Specific Aim 3: Role of extrinsic stimuli in the development of HAART-induced cardiomyopathy.